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Gámez-Díaz, Laura; August, Dietrich; Stepensky, Polina; Revel-Vilk, Shoshana; Seidel, Markus G.; Noriko, Mitsuiki; Morio, Tomohiro; Worth, Austen J. J.; Blessing, Jacob; Veerdonk, Frank van de; Feuchtinger, Tobias; Kanariou, Maria; Schmitt-Graeff, Annette; Jung, Sophie; Seneviratne, Suranjith; Burns, Siobhan; Belohradsky, Bernd H.; Rezaei, Nima; Bakhtiar, Shahrzad; Speckmann, Carsten; Jordan, Michael; Grimbacher, Bodo (2016): The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. In: Journal of Allergy and Clinical Immunology, Vol. 137, No. 1: pp. 223-230
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Abstract

Background: LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by biallelic mutations in LRBA that abolish LRBA protein expression. Objective: We sought to report the extended phenotype of LRBA deficiency in a cohort of 22 LRBA-deficient patients. Methods: Clinical criteria, protein detection, and genetic sequencing were applied to diagnose LRBA deficiency. Results: Ninety-three patients met the inclusion criteria and were considered to have possible LRBA deficiency. Twenty-four patients did not express LRBA protein and were labeled as having probable LRBA deficiency, whereas 22 were genetically confirmed as having definitive LRBA deficiency, with biallelic mutations in LRBA. Seventeen of these were novel and included homozygous or compound heterozygous mutations. Immune dysregulation (95%), organomegaly (86%), recurrent infections (71%), and hypogammaglobulinemia (57%) were the main clinical complications observed in LRBA-deficient patients. Although 81% of LRBA-deficient patients had normal T-cell counts, 73% had reduced regulatory T (Treg) cell numbers. Most LRBA-deficient patients had low B-cell subset counts, mainly in switched memory B cells (80%) and plasmablasts (92%), with a defective specific antibody response in 67%. Of the 22 patients, 3 are deceased, 2 were treated successfully with hematopoietic stem cell transplantation, 7 are receiving immunoglobulin replacement, and 15 are receiving immunosuppressive treatment with systemic corticosteroids alone or in combination with steroid-sparing agents. Conclusion: This report describes the largest cohort of patients with LRBA deficiency and offers guidelines for physicians to identify LRBA deficiency, supporting appropriate clinical management.